Synthesis Of Anticancer Drug Imatinib And Molecular Design Of Its Analogs

Gleevec(Glivec) namely Imatinib mesylate, a kind of N-phenyl-2-pyrimidine-amine derivative, is a specifically molecular targeted selective inhibitor of tyrosine kinase(TK) and as such is an effective therapy for chronic myelogenous leukemia(CML).We now succeeded in obtaining Imatinib base using a convenient method consisting of one traditional synthetic route:esterification, Claisen condensation, ketone-type decomposition, aldol condensation, addition, cyclization, reduction, ammonolysis, nucleophilic substitution, et al.12steps altogether from nicotinic acid. In addition, synthetic processes of key intermediates were preliminary optimized and improvements on esterification, Claisen condensation, ketone-type decomposition, aldol condensation, nitration on aromatic ring, solvent in preparation of guanidine nitrate, reduction method of nitro-compound, solvents and materials in ammonolysis of acyl chloride and halohydrocarbon were also carried out. Compared to other literature methods, yields of each step after optimization and improvement were enhanced, and this method with advantages of simpler operation and less pollution to the environment.Moreover, an improving synthetic route for preparing Imatinib was provided to avoid using the highly toxic and corrosive reagent cyanamide in traditional route, where2-chloro-pyrimidine reacted with corresponding aromatic amine to obtain key intermediate:N-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl)-pyrimidin-2-amine. The processes of diazotization and Cl-substitution of diazonium group to synthesize of2-chloro-pyrimidine were also studied. The whole synthesis is friendly to the environment.Besides the synthesis of Imatinib base, according to drug resistance appeared in Imatinib, molecular design of TKI based on the crystal structure of Imatinib and TK complex(PDB ID:2HYY) was carried out by De Novo Drug Design method.199molecules were obtained by LigBuilder software at first, and10molecules with high score were screened by eHiTS softwares, which can be used as the compounds in later experimental research. We hope that this research can provide efficient TKI drugs of Imatinib analogs with high activities and no resistance.